Method for treating liver dysfunction

ABSTRACT

A method for treating liver dysfunction includes administering at least one member selected from a chitin oligosaccharide, a chitosan oligosaccharide and salts thereof, in an effective amount. As the chitin oligosaccharide, preferred is an oligosaccharide having a degree of polymerization of from 2 to 7. As the chitosan oligosaccharide, preferred is an oligosaccharide having a degree of polymerization of from 2 to 8. As the method for administration, it is preferred to add these oligosaccharides to foods, medicines or feeds, and to orally ingest them. However, when used as medicines, administration methods such as intravenous injection and muscular injection may be used.

RELATED APPLICATION DATA

This application is a division of application Ser. No. 09/060,381, filed on Apr. 15, 1998. This related application is relied on and incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

The present invention relates to a method for treating liver dysfunction.

In recent years, in Japan, reflecting the progressive increase in elderly population and the westernization of diet, the incidence of various diseases in the adult population has increased. One of these diseases is diabetes, which is a generic term for chronic high blood glucose and various complications (such as retinopathy, neuropathy, nephropathy and immune disorder) induced by capillary dysfunction accompanying the chronic high blood glucose. It is estimated that domestically about five million patients are suffering from these diabetes conditions. Diabetes is generally classified into insulin dependent diabetes mellitus (IDDM) and non insulin dependent diabetes mellitus (NIDDM). In Japan, it is reported that IDDM patients account for at most 5% of the diabetes patients, while NIDDM patients account for at least 95% of the diabetes patients. Particularly, NIDDM, which is related to habitat factors such as obesity, overfeeding, ataxia and senescence, is expected to increase in the future in Japan where the progressive increase in elderly population and the westernization of diet will further advance.

As the causes of IDDM, it is generally known that viral infection or defects of the autoimmunization mechanism cause inflammation of the Langerhaus islet of the pancreas, resulting in the destruction of beta-cells as the insulin-producing cells, whereby insulin will not be secreted. This develops IDDM. Accordingly, treatment is made by administration of insulin.

Further, as the causes of NIDDM, it is believed that although insulin is secreted, the action of the insulin on the cells is inadequate, whereby the cells can not sufficiently take glucose in the blood, and a hyperglycemia state is thereby continued. Accordingly, for the treatment, insulin is not necessarily required, and dietary treatment and excercise treatment are mainly used.

If the hyperglycemia state is continued by diabetes, systemic capillaries will fall into disorder and arteriosclerosis will advance, thereby causing obstruction of blood vessels in the heart or brain and gangrene of the legs. Further, if the blood glucose level is high, glucose in the blood is likely to bond to proteins in hemoglobin or tissues, whereby the functions thereof will be inhibited. As the results, complications such as retinopathy, nephropathy, neurosis, cerebral infarction, myocardial infarction and cataracts occur. Further, because immunization power is decreased by diabetes, the patients are likely to catch infections easily.

If the complications become worse, recovery is very difficult, and it is thereby important for diabetes patients to control their blood glucose level so that it will not rise above such level that no symptom is observed. For such a purpose, various antidiabetic agents, such as hypoglycemic agents, have heretofore been developed. For example, there may be mentioned, as natural materials, a hypoglycemic agent containing, as an active ingredient, tea lactone as a water-soluble polysaccharide component of tea leaves (Japanese Unexamined Patent Publication No. 4-124139), an antidiabetic agent containing, as an active ingredient, a hot water extracted fraction of banaba leaves (Japanese Unexamined Patent Publication No. 7-228539), a hypoglycemic agent of a xanthone extracted and isolated from Japanese green gentian (Japanese Unexamined Patent Publication No. 7-206673), and the like; and as chemically synthesized products, a moranolin N-substituted derivative (Japanese Examined Patent Publication No. 59-43949), a thiazolidine compound (Japanese Unexamined Patent Publication No. 4-210977) and a condensed 7-membered cyclic compound having an imidazolyl group (Japanese Unexamined Patent Publication No. 4-178381), and the like.

The chemically synthesized products generally exhibit potent effects, but give unwanted side effects, whereby long term administration gives rise to many problems. While the natural extracted products are high in safety, they typically exhibit inadequate effects.

With respect to liver dysfunction as another one of the diseases of adult people, the liver plays important rolls in vivo, for example, in detoxication, metabolism or storage of sugar, protein or lipid, and hormone control. Dysfunction of the liver often leads to fatal results for living bodies. It is well known that the causes of liver dysfunction represented by hepatitis are based on the habits of life, for example, over ingestion of alcoholic beverages, heavy drinking, heavy eating, irregular life or stress. However, it has been found that liver dysfunction is often caused by the hepatitis virus. Moreover, if viral hepatitis becomes chronic, it will often become hepatic carcinoma through liver cirrhosis, for which a suitable treatment method has been demanded.

Many proposals have heretofore been made as a treatment agent for hepatitis. However, chemically synthesized products generally exhibit potent effects, but have side effects, thereby being problematic for long term administration. Natural extracted products are high in safety, but they do not exhibit adequate effects.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method for treating liver dysfunction which is high in safety and gives adequate effects.

Another aspect of the present invention is to provide a method for treating liver dysfunction which comprises administering at least one member selected from the group consisting of a chitin oligosaccharide, a chitosan oligosaccharide and salts thereof, in an effective amount.

According to the present invention, as indicated in the test examples as shown below, with respect to mice suffering from an artificially induced hepatitis, significant treatment effects, i.e., lessening the symptoms, can be observed. Accordingly, it is expected that the method of the invention will show an improving effect or effects on treating liver dysfunction accompanying hepatitis or the like during treatment of animals, including humans.

The chitin oligosaccharide, chitosan oligosaccharide and salts thereof used for these methods are obtained from polysaccharides as starting materials present abundantly in nature, and thereby are high in safety and can be produced by relatively simple steps, such being advantageous in production costs.

Further, the chitin oligosaccharide, chitosan oligosaccharide and salts thereof are easily dissolved in water, whereby they are easily handled, and readily ingested in daily life by adding them, for example, to foods and drinks.

BRIEF EXPLANATION OF THE DRAWINGS

FIG. 1 is a graph showing the change of the blood glucose level in the animals used in Test Example 1 wherein the effects of chitosan administration on the non insulin dependent diabetes mellitus of mice were examined.

FIG. 2 is a graph showing the change of the body weight in animals used in Test Example 1.

FIG. 3 is a graph showing the change of the ingested amount of feed in animals used in Test Example 1.

FIG. 4 is a graph showing the change of the ingested amount of water in animals used in Test Example 1.

FIG. 5 is a graph showing the change of the blood glucose level in the animals used in Test Example 2 wherein the effects of chitin oligosaccharide or chitosan oligosaccharide administration on the non insulin dependent diabetes mellitus of mice were examined.

FIG. 6 is a graph showing the change of the body weight in animals used in Test Example 2.

FIG. 7 is a graph showing the change of the ingested amount of feed in animals used in Test Example 2.

FIG. 8 is a graph showing the change of the ingested amount of water in animals used in Test Example 2.

FIG. 9(a) is a microscopic photograph showing a liver tissue of a mouse of a control group in an experiment of induced hepatitis using mice, with magnification of 100 times.

FIG. 9(b) is a microscopic photograph showing a liver tissue of a mouse of a control group in an experiment of induced hepatitis using mice, with magnification of 400 times.

FIG. 10(a) is a microscopic photograph showing a liver tissue of a mouse of a group to which a chitin oligosaccharide mixture was administered in an experiment of induced hepatitis using mice, with magnification of 100 times.

FIG. 10(b) is a microscopic photograph showing a liver tissue of a mouse of a group to which a chitin oligosaccharide mixture was administered in an experiment of induced hepatitis using mice, with magnification of 400 times.

FIG. 11(a) is a microscopic photograph showing a liver tissue of a mouse of a group to which a chitosan oligosaccharide acetate mixture was administered in an experiment of induced hepatitis using mice, with magnification of 100 times.

FIG. 11(b) is a microscopic photograph showing a liver tissue of a mouse of a group to which a chitosan oligosaccharide acetate mixture was administered in an experiment of induced hepatitis using mice, with magnification of 400 times.

PREFERRED EMBODIMENTS OF THE INVENTION

Now, the present invention will be explained in detail with reference to preferred embodiments.

The chitin oligosaccharide, chitosan oligosaccharide and salts thereof used in the present invention are obtained by chemically or biochemically treating chitin which is prepared from, for example, shells of crustaceans such as crab, lobster or shrimp by a conventional method.

Namely, the chitin oligosaccharide is obtained by subjecting chitin to partial hydrolysis with an acid or an enzyme, and if the case requires, fractionating or purifying the portion with the desired degree of polymerization from the hydrolyzate by a method such as column chromatography or solvent fractionation. As the method of hydrolysis with an acid, for example, a method described in Japanese Examined Patent Publication No. 5-86399 by the present applicant, may preferably be used. As the degree of polymerization of the chitin oligosaccharide, preferred are ones at a level of from disaccharide to heptasaccharide, i.e. N-acetylchitobiose, N-acetylchitotriose, N-acetylchitotetrose, N-acetylchitopentose, N-acetylchitohexose and N-acetylchitoheptose. Among them, one or a mixture of at least two of them may preferably be used. In this connection, the chitin oligosaccharide or its mixture commercially sold by the companies in this field, and, for example, “NA-COS-Y” (trade name, manufactured by Yaizu Suisan Kagaku Kogyo Kabushiki Kaisha) may be used.

The chitosan oligosaccharide is obtained by partially hydrolyzing chitosan which is obtained by subjecting chitin to a hot concentrated alkali treatment. The partial hydrolysis of chitosan is carried out, for example, by a method wherein chitosan is heated together with an acid such as hydrochloric acid, acetic acid or formic acid, and then the acid is removed or neutralization and desalting are conducted, followed by, for example, crystallization to form a powder, or a method wherein chitosan is dissolved in a dilute acid, and then, for example, chitosanase or D-glucosaminidase is allowed to react thereto. The degree of polymerization of the chitosan oligosaccharide obtained by such a method is usually at a level of from disaccharide to octasaccharide, i.e., mixtures of, for example, chitobiose, chitotriose, chitotetrose, chitopentose, chitohexose, chitoheptose and chitooctose. In the present invention, it is possible to use the chitosan oligosaccharides in the mixture state as mentioned above. However, it is also possible to subject such a mixture to fractionation and purification to obtain the portion having the desired degree of polymerization by a method such as column chromatography or solvent fractionation. In this connection, the chitosan oligosaccharide or its mixture commercially sold by the companies in this field, and, for example, “COS-Y” (trade name, manufactured by Yaizu Suisan Kagaku Kogyo Kabushiki Kaisha) may be used.

Further, in the present invention, as the salts of the chitin oligosaccharide and chitosan oligosaccharide, inorganic acid salts such as hydrochlorides and sulfates, and organic acid salts such as acetates, lactates and formates, may, for example, preferably be used.

The method for treating liver dysfunction of the present invention is characterized by administering at least one member selected from the group consisting of a chitin oligosaccharide, a chitosan oligosaccharide and salts thereof, in an effective amount. The method for treating liver dysfunction of the present invention can be applied to not only humans, but also to various animals such as pets or livestock. As the method for administration, it is preferred to add at least one member selected from the group consisting of a chitin oligosaccharide, a chitosan oligosaccharide and salts thereof, to foods, medicines or feeds, and orally ingest them. However, when used as medicines, administration methods such as intravenous injection and muscular injection, may be applied. Because the chitin oligosaccharide, chitosan oligosaccharide and salts thereof are readily dissolved in water, the addition to foods, medicines or feeds can easily be made.

In the method for treating liver dysfunction of the present invention, the dose of the chitin oligosaccharide, chitosan oligosaccharide or salts thereof, is preferably, as the chitin oligosaccharide or chitosan oligosaccharide, 0.1 to 1,000 mg in the case of oral administration, from 0.01 to 100 mg in the case of intravenous injection, and from 0.01 to 100 mg in the case of muscular injection, per kg of body weight. Further, the incorporated amount, for example, to foods, medicines and feeds, is preferably from 0.01 to 10 wt %.

The safety of the chitin oligosaccharide and chitosan oligosaccharide has already been confirmed. For example, results of acute toxicity tests show that the safeties of both polysaccharides are LD₅₀>5 g/kg in the case of oral administration in rats.

Hereinafter, the present invention will be described in further detail with reference to examples. However, it should be understood that the present invention is by no means restricted by these examples.

EXAMPLE 1

(Preparation of a chitin oligosaccharide mixture)

To 1,000 g of chitin derived from crab shells, 4,000 ml of 12N hydrochloric acid was added. Stirring was conducted in a water bath at 45° C. for 3 hours, and then 4,000 ml of water was added thereto, and the reaction was terminated. After neutralization to pH 6.0 with 25% caustic soda, decoloring with activated carbon, filtration and desalting by electrodialysis were conducted. After purification by a treatment with ion exchange resins, spray drying was conducted to obtain 420 g of a chitin oligosaccharide mixture.

The composition of this chitin oligosaccharide mixture was 35 wt % of N-acetylglucosamine, 19 wt % of N-acetylchitobiose, 15 wt % of N-acetylchitotriose, 12 wt % of N-acetylchitotetrose, 8 wt % of N-acetylchitopentose, 6 wt % of N-acetylchitohexose and 5 wt % of N-acetylchitoheptose.

EXAMPLE 2

(Preparation of a chitosan oligosaccharide mixture)

To 100 g of chitosan derived from crab shells, 400 ml of 12N hydrochloric acid was added. Stirring was conducted in a water bath at 70° C. for 2 hours, and then 400 ml of water was added thereto, and the reaction was terminated. Insolubles were removed by filtration with a filter. Then, 10 g of activated charcoal was added and stirring was conducted for 1 hour, followed by filtration with a filter for removal of the activated charcoal to obtain 700 ml of a separated and decolored liquid. This separated and decolored liquid was concentrated under reduced pressure while distilling the hydrochloric acid off. To the obtained syrup-like condensate, 300 ml of methanol was added and further 900 ml of acetone was added, to deposit a crystalline precipitate. This precipitate was collected by filtration with a filter, and dried in vacuum to obtain 120 g of a chitosan oligosaccharide mixture.

The glucose composition of this chitosan oligosaccharide mixture was 32 wt % of glucosamine, 20 wt % of chitobiose, 14 wt % of chitotriose, 14 wt % of chitotetrose, 10 wt % of chitopentose, 4 wt % of chitohexose, 4 wt % of chitoheptose and 2 wt % of chitooctose.

EXAMPLE 3

(Preparation of a chitosan oligosaccharide acetate mixture)

To 250 g of chitosan derived from crab shells, 5 liters of water and 90 g of glacial acetic acid were added, followed by stirring for one night to obtain a viscous solution. To this chitosan solution, 50 mg of chitosanase (manufactured by Meiji Seika Kabushiki Kaisha) derived from Bachillus pumilus was added, and stirring was conducted in a water bath at 40° C. for 18 hours. After completion ofthe reaction, heating was conducted at 80° C. for 10 minutes to deactivate the enzyme, to obtain a chitosan oligosaccharide solution. Then, the chitosan oligosaccharide solution was spray dried to obtain 210 g of a chitosan oligosaccharide acetate mixture.

The glucose composition of this chitosan oligosaccharide acetate mixture was 25 wt % of chitobiose acetate, 24 wt % of chitotriose acetate, 19 wt % of chitotetrose acetate, 16 wt % of chitopentose acetate, 8 wt % of chitohexose acetate, 5 wt % of chitoheptose acetate and 3 wt % of chitooctose acetate.

TEST EXAMPLE 1

(Effects of chitosan administration on mice of induced NIDDM)

Firstly, for comparison, the effects of chitosan as a polysaccharide on mice suffering from diabetes were examined. As a model mouse of diabetes, C57BL/KsJ db/db mouse (hereinafter referred to as “db mouse”) was used. It is known that this mouse has an abnormality in the central nervous system for appetite and shows obesity by over eating in an early stage, whereby NIDDM accompanying a high blood glucose tends to occur.

To the db mice (n=7), a commercially available feed for breeding (trade name “CE-2”, manufactured by Nippon Clea) to which 2 wt % of chitosan was blended, was given from the age of 4 weeks old. To the db mice (n=7) of a control group, the same feed containing no chitosan was given. For each of these mice, the blood glucose level was measured every two weeks, and the average body weight and the average ingested amounts of the feed and water were measured every week. The blood glucose level was measured by a hexonase test paper method using “Titex” (trade name, manufactured by Ono Pharmaceutical K.K.).

As the results of the above tests, FIG. 1 shows the change of the blood glucose level, FIG. 2 shows the change of the average body weight, and FIG. 3 and FIG. 4 show the change of the average ingested amounts of the feed and water, respectively. According to the results, the chitosan-ingesting group tended to display a reduced blood glucose level, average body weight and average ingested amount of water as compared with the control group. Nevertheless, statistically, no significance was admitted.

TEST EXAMPLE 2

(Effects of chitin oligosaccharide or chitosan oligosaccharide administration on mice of induced NIDDM)

To 8 week old db mice, a commercially available feed for breeding “CE-2” was given as used in TEST EXAMPLE 1. To one group of the mice (n=18), water containing 0.5 wt % of the chitin oligosaccharide prepared in Example 1 was given, and to another group of the mice (n=18), water containing 0.5 wt % of the chitosan oligosaccharide acetate prepared in Example 2 was given. All of the chitin oligosaccharide-ingesting group, the chitosan oligosaccharide acetate-ingesting group and the non-ingesting group (n=21), were grown until 30 weeks old, during which time the blood glucose level was measured every two weeks, and the average body weight and the average ingested amounts of the feed and water were measured every week.

Further, the tissue image of the pancreas at 30 weeks old was inspected. FIG. 5 shows the change of the blood glucose level, FIG. 6 shows the change of the average body weight, and FIG. 7 and FIG. 8 show the change of the average ingested amounts of the feed and water, respectively.

The results are as follows:

(1) Blood glucose level:

The blood glucose levels of the chitin oligosaccharide-ingesting group and the chitosan oligosaccharide acetate-ingesting group changed at a significantly low level from 12 to 30 weeks old (p<0.01) as compared with the blood glucose level of the non-ingesting group, as shown in FIG. 5. Until 18 weeks old, the blood glucose level of the non-ingesting group shows a tendency to increase, whereas the blood glucose level of the chitosan oligosaccharide acetate-ingesting group shows a tendency to decrease.

(2) Average body weight:

The average body weight of the chitosan oligosaccharide acetate-ingesting group changed at a low level until 22 weeks old as shown in FIG. 6. (Significance was admitted at the age of 11, 12, 15 and 16 weeks old (p<0.05)). The average body weight of the non-ingesting group showed a tendency to decrease after 22 weeks old, while the chitosan oligosaccharide acetate-ingesting group showed a tendency to increase, whereby the average body weights of these groups were substantially the same at 30 weeks old. On the other hand, the average body weight of the chitin oligosaccharide-ingesting group changed at a low level (significance was admitted at 11, 12, 15 and 16 weeks old (p<0.05)). However, after 22 weeks old, the average body weight of the non-ingesting group showed a tendency to decrease and was thereby substantially the same as that of the chitosan oligosaccharide acetate-ingesting group at 30 weeks old.

(3) Average ingested amounts of feed and water:

The average ingested amounts of feed and water of the chitin oligosaccharide-ingesting group and the chitosan oligosaccharide acetate-ingesting group were suppressed as compared with the non-ingesting group during the period between 9 to 30 weeks old (FIGS. 7 and 8). The average ingested amount of water was remarkably suppressed.

TEST EXAMPLE 3

(Preparatory experiment concerning induced-hepatitis in mice)

To each of mice (BDFL) of 8 weeks old, fungi of Corynebacterium parvinu were intravenously administered in an amount of 0.5 mg/mouse, and 7 days later, a lipopolysaccharide (LPS) extracted from Escherichia coli was intravenously administered in an amount of 0.1 mg, 1 mg or 10 mg/mouse. Then, each group was inspected by the 21 st day, and sacrificed to investigate the condition of hepatitis. The results are shown in Table 1.

TABLE 1 Dose of LPS Conditions of mice Degree of hepatitis  10 mg All mice died in the 8^(th) Not detected or 9^(th) day   1 mg 50% died by the 14^(th) day Potent hepatitis induced 0.1 mg All mice survived until the Weak hepatitis induced 21^(st) day

If fungi of corynebacterium is intravenously administered and, one week later, LPS is intravenously administered, gyangrene of liver cells occurs and hepatitis is induced. It has been believed that this is because macrophage is placed in the primed condition with the coryiebacteriiuni (a condition liable to react to stimulation). This method has been established as a liver disorder model from the old time. Further, the mouse (BDFL) is a cross first generation mouse obtained by mating a female C57BL mouse and a male DBA/2 mouse.

TEST EXAMPLE 4

(Effects of chitin olitosaccharide or chitosan oligosaccharide administration on experimental acute hepatitis)

0.1 mg/mouse of LPS was administered to mice by injection to induce acute hepatitis as described in TEST EXAMPLE 3, and one week later (at the 14th day from the initiation of the test), the chitin oligosaccharide mixture obtained in EXAMPLE 1 or the chitosan olindosaccharide acetate mixture obtained in EXAMPLE 3 was added to the water in an amount of 0.5 mg/ml, respectively, and the mice were permitted to freely ingest it. At the 28th day, the mice were sacrificed, and a part of the liver was taken out and subjected to histopatholosical inspection. Namely, assuming that a colony of lymphoblasts is a lesion portion (unit), the number of the units in a section of the liver was counted and the number of the colonies of lymphoblasts in one unit was counted to evaluate the size of the lesion. The results of these tests are shown in Table 2.

TABLE 2 The Number The Number of Lymphoblasts in No. of Sample of Lesions the Largest Lesion Portion Control 1 26 31 group 2 42 101 3 45 79 4 41 45 5 45 56 6 22 39 7 25 34 Group to which 8 27 41 chitosan oligo- 9 26 44 saccharide acetate 10 22 72 mixture 11 19 20 (EXAMPLE 3) was 12 24 38 administered 13 12 28 14 26 30 Group to which 15 26 44 chitin oligo- 16 37 50 saccharide mixture 17 29 48 (EXAMPLE 1) was 18 17 39 administered 19 10 60 20 10 44

Table 2 shows the number of lesions found in a section of the liver of each mouse and the number of lymphoblasts found in the largest lesion. As evident from the results, as compared with the control group to which water was simply given, the group to which the chitin oligosaccharide mixture was administered and the group to which the chitosan oligosaccharide acetate mixture was administered show a lower number of lesions, whereby the effects for treating hepatitis are observed.

Further, photographs of typical liver sections of the respective groups were taken by an optical microscope (trade name: “Olympus Vanox”, manufactured by Olympus Kogaku Kogyo K.K.). The optical microscopic photographs showing the tissue images are shown in FIGS. 9(a) to 11(b).

FIGS. 9(a) and 9(b) show the control group. FIG. 9(a) is a microscopic photograph with magnification of 100 times. FIG. 9(b) is a microscopic photograph with magnification of 400 times.

FIGS. 10(a) and 10(b) show the group to which a chitin oligosaccharide mixture (Example 1) was administered. FIG. 10(a) is a microscopic photograph with magnification of 100 times. FIG. 10(b) is a microscopic photograph with magnification of 400 times.

FIGS. 11(a) and 11(b) show the group to which a chitosan oligosaccharide acetate mixture (Example 3) was administered. FIG. 11(a) is a microscopic photograph with magnification of 100 times. FIG. 11(b) is a microscopic photograph with magnification of 400 times.

From these photographs also, as compared with the control group to which water was simply given, the group to which the chitin oligosaccharide mixture was administered and the group to which the chitosan oligosaccharide acetate mixture was administered show a lower number of lesions, whereby the effects for treating hepatitis are observed. 

What is claimed is:
 1. A method for treating liver dysfunction, which comprises: administering at least one member selected from the group consisting of a chitin oligosaccharide, a chitosan oligosaccharide, and salts thereof, in an effective amount, wherein when the member administered includes at least one chitin oliyosaccharide, the chitin oligosaccharide or oligosaccharides have a degree of polymerization of from 2 to 7, and when the member administered includes at least one chitosan oligosaccharide, the chitosan oligosaccharide or oligosaccharides have a degree of polymerization of from 2 to
 8. 2. The method for treating liver dysfunction according to claim 1, wherein the member administered is at least one chitin oligosaccharide with a degree of polymerization of from 2 to 7, or salts thereof.
 3. The method for treating liver dysfunction according to claim 1, wherein the member administered is at least one chitosan oligosaccharide with a degree of polymerization of from 2 to 8, or salts thereof.
 4. The method for treating liver dysfunction according to claim 1, wherein the administration is oral administration.
 5. The method for treating liver dysfunction according to claim 4, wherein the member is administered in a dose of 0.1 to 1000 mg per kilogram of body weight.
 6. The method for treating liver dysfunction according to claim 1, wherein the member is administered in a dose of 0.1 to 1000 mg per kilogram of body weight.
 7. The method for treating liver dysfunction according to claim 1, wherein the member is administered in a dose of 0.01 to 100 mg per kilogram of body weight.
 8. The method for treating liver dysfunction according to claim 1, wherein the member is administered as an inorganic acid salt selected from the group consisting of hydrochlorides and sulfates.
 9. The method for treating liver dysfunction according to claim 1, wherein the member is administered as an organic acid salt selected from the group consisting of acetates, lactates, and formates. 